Breath biomarkers in idiopathic pulmonary fibrosis: a systematic review.

BACKGROUND: Exhaled biomarkers may be related to disease processes in idiopathic pulmonary fibrosis (IPF) however their clinical role remains unclear. We performed a systematic review to investigate whether breath biomarkers discriminate between patients with IPF and healthy controls. We also assessed correlation with lung function, ability to distinguish diagnostic subgroups and change in response to treatment. METHODS: MEDLINE, EMBASE and Web of Science databases were searched. Study selection was limited to adults with a diagnosis of IPF as per international guidelines. RESULTS: Of 1014 studies screened, fourteen fulfilled selection criteria and included 257 IPF patients. Twenty individual biomarkers discriminated between IPF and controls and four showed correlation with lung function. Meta-analysis of three studies indicated mean (± SD) alveolar nitric oxide (CalvNO) levels were significantly higher in IPF (8.5 ± 5.5 ppb) than controls (4.4 ± 2.2 ppb). Markers of oxidative stress in exhaled breath condensate, such as hydrogen peroxide and 8-isoprostane, were also discriminatory. Two breathomic studies have isolated discriminative compounds using mass spectrometry. There was a lack of studies assessing relevant treatment and none assessed differences in diagnostic subgroups. CONCLUSIONS: Evidence suggests CalvNO is higher in IPF, although studies were limited by small sample size. Further breathomic work may identify biomarkers with diagnostic and prognostic potential.

The detection, assessment and clinical evolution of interstitial lung abnormalities identified through lung cancer screening.

Introduction: Interstitial lung abnormalities (ILAs) are common incidental findings in lung cancer screening; however, their clinical evolution and longer-term outcomes are less clear. The aim of this cohort study was to report 5-year outcomes of individuals with ILAs identified through a lung cancer screening programme. In addition, we compared patient-reported outcome measures (PROMs) in patients with screen-detected ILAs to newly diagnosed interstitial lung disease (ILD) to assess symptoms and health-related quality of life (HRQoL). Methods: Individuals with screen-detected ILAs were identified, and 5-year outcomes, including ILD diagnoses, progression-free survival and mortality, were recorded. Risk factors associated with ILD diagnosis were assessed using logistic regression and survival using Cox proportional hazard analysis. PROMs were compared between a subset of patients with ILAs and a group of ILD patients. Results: 1384 individuals underwent baseline low-dose computed tomography screening, with 54 (3.9%) identified as having ILAs. 22 (40.7%) were subsequently diagnosed with ILD. 14 (25.9%) individuals died, and 28 (53.8%) suffered disease progression within 5 years. Fibrotic ILA was an independent risk factor for ILD diagnosis, mortality and reduced progression-free survival. Patients with ILAs had lower symptom burden and better HRQoL in comparison to the ILD group. Breathlessness visual analogue scale (VAS) score was associated with mortality on multivariate analysis. Conclusions: Fibrotic ILA was a significant risk factor for adverse outcomes including subsequent ILD diagnosis. While screen-detected ILA patients were less symptomatic, breathlessness VAS score was associated with adverse outcomes. These results could inform risk stratification in ILA.

Changes in lung epithelial cell volatile metabolite profile induced by pro-fibrotic stimulation with TGF-ß1.

Volatile organic compounds (VOCs) have shown promise as potential biomarkers in idiopathic pulmonary fibrosis. Measuring VOCs in the headspace ofin vitromodels of lung fibrosis may offer a method of determining the origin of those detected in exhaled breath. The aim of this study was to determine the VOCs associated with two lung cell lines (A549 and MRC-5 cells) and changes associated with stimulation of cells with the pro-fibrotic cytokine, transforming growth factor (TGF)-ß1. A dynamic headspace sampling method was used to sample the headspace of A549 cells and MRC-5 cells. These were compared to media control samples and to each other to identify VOCs which discriminated between cell lines. Cells were then stimulated with the TGF-ß1 and samples were compared between stimulated and unstimulated cells. Samples were analysed using thermal desorption-gas chromatography-mass spectrometry and supervised analysis was performed using sparse partial least squares-discriminant analysis (sPLS-DA). Supervised analysis revealed differential VOC profiles unique to each of the cell lines and from the media control samples. Significant changes in VOC profiles were induced by stimulation of cell lines with TGF-ß1. In particular, several terpenoids (isopinocarveol, sativene and 3-carene) were increased in stimulated cells compared to unstimulated cells. VOC profiles differ between lung cell lines and alter in response to pro-fibrotic stimulation. Increased abundance of terpenoids in the headspace of stimulated cells may reflect TGF-ß1 cell signalling activity and metabolic reprogramming. This may offer a potential biomarker target in exhaled breath in IPF.

Transbronchial Lung Cryobiopsy in Idiopathic Pulmonary Fibrosis: A State of the Art Review.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease associated with significant morbidity and mortality. The diagnosis of IPF involves a combination of clinical history, radiological imaging and examination of histopathological samples in appropriate cases. Historically, transbronchial biopsy (TBB) has been used to obtain histological samples; however this lacks diagnostic accuracy. At present, surgical lung biopsy (SLB) is the gold standard technique for obtaining specimen samples; however this carries a significant mortality risk. Transbronchial lung cryobiopsy (TBLC) is a new technique that has been pioneered in the management of lung malignancy and offers a potential alternative to SLB. The technique employs a freezing probe, which is used to obtain lung tissue samples that are larger and better quality than traditional TBB samples. This affords TBLC an estimated diagnostic yield of 80% in interstitial lung disease. However, with limited evidence directly comparing TBLC to SLB, the diagnostic accuracy of the procedure has been uncertain. Common complications of TBLC include pneumothorax and bleeding. Mortality in TBLC is low compared with SLB, with exacerbation of IPF frequently reported as the cause. TBLC represents an exciting potential option in the diagnostic pathway in IPF; however its true value has yet to be determined.

The role of measuring exhaled breath biomarkers in sarcoidosis: a systematic review.

INTRODUCTION: Sarcoidosis is a chronic granulomatous disease of unknown aetiology with a variable clinical course and prognosis. There is a growing need to identify non-invasive biomarkers to differentiate between clinical phenotypes, identify those at risk of disease progression and monitor response to treatment. OBJECTIVES: We undertook a systematic review and meta-analysis to evaluate the utility of breath-based biomarkers in discriminating sarcoidosis from healthy controls, alongside correlation with existing non breath-based biomarkers used in clinical practice, radiological stage, markers of disease activity and response to treatment. METHODS: Electronic searches were undertaken during November 2017 using PubMed, Ebsco, Embase and Web of Science to capture relevant studies evaluating breath-based biomarkers in adult patients with sarcoidosis. RESULTS: 353 papers were screened; 21 met the inclusion criteria and assessed 25 different biomarkers alongside VOCs in exhaled breath gas or condensate. Considerable heterogeneity existed amongst the studies in terms of participant characteristics, sampling and analytical methods. Elevated biomarkers in sarcoidosis included 8-isoprostane, carbon monoxide, neopterin, TGF-ß1, TNFα, CysLT and several metallic elements including chromium, silicon and nickel. Three studies exploring VOCs were able to distinguish sarcoidosis from controls. Meta-analysis of four studies assessing alveolar nitric oxide showed no significant difference between sarcoidosis and healthy controls (2.22 ppb; 95% CI -0.83, 5.27) however, a high degree of heterogeneity was observed with an I 2 of 93.4% (p < 0.001). Inconsistent or statistically insignificant results were observed for correlations between several biomarkers and radiological stage, markers of disease activity or treatment. CONCLUSIONS: The evidence for using breath biomarkers to diagnose and monitor sarcoidosis remains inconclusive with many studies limited by small sample sizes and lack of standardisation. VOCs have shown promising potential but further research is required to evaluate their prognostic role.

Idiopathic Pulmonary Fibrosis (IPF): An Overview.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterised by chronic, progressive scarring of the lungs and the pathological hallmark of usual interstitial pneumonia. Current paradigms suggest alveolar epithelial cell damage is a key initiating factor. Globally, incidence of the disease is rising, with associated high morbidity, mortality, and economic healthcare burden. Diagnosis relies on a multidisciplinary team approach with exclusion of other causes of interstitial lung disease. Over recent years, two novel antifibrotic therapies, pirfenidone and nintedanib, have been developed, providing treatment options for many patients with IPF, with several other agents in early clinical trials. Current efforts are directed at identifying key biomarkers that may direct more customized patient-centred healthcare to improve outcomes for these patients in the future.

Nintedanib in the management of idiopathic pulmonary fibrosis: clinical trial evidence and real-world experience.

Idiopathic pulmonary fibrosis (IPF) is a fibrotic interstitial lung disease associated with significant morbidity and mortality. Previously, IPF has been managed using immunosuppressive therapy; however, it has been shown that this is associated with increased mortality. In the last 5 years, two disease-modifying agents have been licensed for use in IPF, namely pirfenidone and nintedanib. Nintedanib is a tyrosine kinase inhibitor with antifibrotic properties that has also been shown to significantly reduce the progression of the disease. The scientific evidence shows that nintedanib is effective and well tolerated for the treatment of IPF in mild, moderate and severe stages of the disease. Real-world experiences also support the findings of previously conducted clinical trials and show that nintedanib is effective for the management of IPF and is associated with reducing disease progression. Gastrointestinal events, mainly diarrhoea, are the main adverse events caused by the treatment. Recent real-word studies also suggest that nintedanib stabilizes lung function till lung transplantation, with no increased surgical complications or postoperative mortality after lung transplantation. In this review, we will discuss the clinical trial evidence and real-world experience for nintedanib in the management of IPF.

Drug-Induced Interstitial Lung Disease: A Systematic Review.

BACKGROUND: Drug-induced interstitial lung disease (DIILD) occurs as a result of numerous agents, but the risk often only becomes apparent after the marketing authorisation of such agents. METHODS: In this PRISMA-compliant systematic review, we aimed to evaluate and synthesise the current literature on DIILD. RESULTS: Following a quality assessment, 156 full-text papers describing more than 6000 DIILD cases were included in the review. However, the majority of the papers were of low or very low quality in relation to the review question (78%). Thus, it was not possible to perform a meta-analysis, and descriptive review was undertaken instead. DIILD incidence rates varied between 4.1 and 12.4 cases/million/year. DIILD accounted for 3⁻5% of prevalent ILD cases. Cancer drugs, followed by rheumatology drugs, amiodarone and antibiotics, were the most common causes of DIILD. The radiopathological phenotype of DIILD varied between and within agents, and no typical radiological pattern specific to DIILD was identified. Mortality rates of over 50% were reported in some studies. Severity at presentation was the most reliable predictor of mortality. Glucocorticoids (GCs) were commonly used to treat DIILD, but no prospective studies examined their effect on outcome. CONCLUSIONS: Overall high-quality evidence in DIILD is lacking, and the current review will inform larger prospective studies to investigate the diagnosis and management of DIILD.

Managing Idiopathic Pulmonary Fibrosis: Which Drug for Which Patient?

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with high mortality. Two novel antifibrotic agents, pirfenidone and nintedanib, have received licences for use in IPF in recent years. Phase III, multinational, randomised control trials have provided evidence that both drugs reduce decline in forced vital capacity (FVC) over time, while further post hoc studies have suggested that both pirfenidone and nintedanib can be efficacious, regardless of age and severity of baseline lung function. Both therapeutic agents have manageable side effect profiles. In the absence of head-to-head data, decisions regarding which agent to choose when starting treatment for IPF should take into consideration joint decision making between patients and clinicians based on accurate information in the decision-making process. Questions remain as to the role of combination antifibrotic therapy as a future treatment option.

Idiopathic pulmonary fibrosis: a holistic approach to disease management in the antifibrotic age.

Idiopathic pulmonary fibrosis (IPF) is the most common cause of interstitial lung disease (ILD) and carries a worse prognosis than many cancers. Until recently, there were no active treatment options available for patients with IPF, meaning palliation or lung transplantation in selected patients were the only options. The management of IPF has changed dramatically over the last decade with the advent of two antifibrotic agents; pirfenidone and nintedanib. These new agents have been shown to reduce decline in lung function and pirfenidone has been shown to reduce mortality. The changing landscape of IPF diagnosis and management present a number of issues that may be encountered including management of side effects related to antifibrotic therapy. This article aims to give an overview of the holistic approach to the management of patients with IPF, including antifibrotic management, symptom management and the invaluable role of the ILD specialist nurse.

Barriers to pulmonary rehabilitation: characteristics that predict patient attendance and adherence.

BACKGROUND: Pulmonary rehabilitation (PR) is efficacious in chronic obstructive pulmonary disease (COPD). As completion rates of PR are poor, we wished to assess predictors of attendance and adherence. METHODS: We performed a retrospective analysis of 711 patients with COPD, who were invited to attend PR. Data were compared to allow predictors (gender, smoking status, attending partner, referral route, employment status, body mass index, forced expiratory volume in 1 s (FEV(1)), oxygen therapy (LTOT), oxygen saturations, chronic respiratory questionnaire (CRQ), shuttle walk distance, travel distance and time) of attendance (0 or >0 attendance) and adherence (< or >63% attendance) to be identified. RESULTS: 31.8% of patients referred for PR did not attend and a further 29.1% were non-adherent. Predictors of non-attendance were female gender, current smoker, and living alone. Predictors of non-adherence were extremes of age, current smoking, LTOT use, FEV(1), CRQ score and travelling distance. Multiple logistic regression revealed that LTOT and living alone were independent predictors of poor attendance and current smoking, poor shuttle walking distance and hospitalisations were independent predictors of poor adherence. CONCLUSION: Smoking status, availability of social support and markers of disease severity were predictors of attendance and adherence to PR.